1. Field of the Invention
This invention relates to a process for producing a C.9 nor-keto FK-506 hydroxide mediated rearrangement product, which is an intermediate for producing an immunosuppressant.
2. Brief Description of Disclosures in the Art
In 1983, the US FDA licensed cyclosporin, an extremely effective anti-rejection drug that revolutionized the field of organ transplant surgery. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein.
As effective as the drug is in fighting transplantation rejection, it suffers drawbacks in causing kidney failure, liver damage and ulcers which in many cases can be very severe.
EPO Publication No. 0184162 to Fujisawa, hereby incorporated by reference, describes a new macrolide immunosuppressant FK-506 which is reputed to be 100 times more effective than cyclosporin. The macrolide is produced by fermentation of a particular strain of Streptomyces tsukubaensis No. 9993 (FERM BP-927). Also described are the closely related macrolide immunosuppressants FK-525, produced by the same microorganism, and FK-520 and FK-523, produced by S. hygroscopicus subsp. yakushimaensis.
The novel 23-membered tricyclo-macrolide FK-506 was isolated and characterized by Tanaka, Kuroda, and co-workers, see JACS, 109, pp. 5031, 1987, and EPO Publication No. 0184162. The potential usefulness of such an agent in bone marrow and organ transplantations coupled with its unique structural features has prompted many in the field to initiate efforts towards the synthesis of FK-506 type macrolide structures, by contacting FK-506, with different chemical reagents under a variety of conditions to produce molecular modifications thereof, some of which may exhibit greater immunosuppressant activity than the naturally occurring form itself.
For example, Tanaka et al (Fujisawa) have reported in J. Am. Chem. Soc., 1987, 108, p. 5031, that alkaline treatment of FK-506 (1) leads to the hydrolysis product 6 assigned structure shown below, which is not described as having immunosuppressant properties. ##STR1##
There is a continuing search for new and more therapeutically effective molecular modifications of FK-506 having diminished adverse and toxic side effects. See for example: (a) Askin, D.; Volante, R. P.; Reamer, R. A.; Ryan, K. M.; Shinkai, I. Tetrahedron Lett., 1988, 29, p. 277; (b) Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Tetrahedron Lett., 1988, 29, p. 281; (c) Desmond, R.; Mills, S. G.; Volante, R. P.; Shinkai I. Tetrahedron Lett., 1988, 29, p. 3895; (d) Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.; Shinkai, I. Tetrahedron Lett., 1988, 29, p. 4245.